JP2019535696A - Pharmaceutical composition of pyridone derivative and method for producing the same - Google Patents

Abstract

The present invention provides a pharmaceutical composition of a pyridone derivative and a method for producing the same. Specifically, the present invention provides a pharmaceutical composition containing a pyridone derivative or a pharmaceutically acceptable salt thereof, and a method for producing the same. The pharmaceutical composition has an active ingredient of 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, Contains 6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof and hydroxypropylmethylcellulose. The dissolution of the pharmaceutical composition is good.

Description

  The present invention belongs to the field of pharmaceutical formulations, specifically 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy)- The present invention relates to a pharmaceutical composition containing 6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof and a method for producing the same.

  Melanoma is the most aggressive type of skin cancer and is the most common cause of death among skin diseases. According to estimates by the National Cancer Institute, 76,690 Americans will be diagnosed with melanoma in 2013, and 9,480 will die from the disease. About half of melanoma patients carry a mutated BRAF protein kinase gene. This abnormal mutation may promote melanoma growth and expansion, with V600 dominating. Unfortunately, prior to 2011, chemotherapy with cytotoxin dacarbazine was the main treatment for malignant melanoma. Dacarbazine is a DNA alkylating drug that has not only significant side effects but also a response rate of about 10%. The one-year survival rate is only about 36%. In 2011, the launch of two groundbreaking new drugs, Yervoy and Zelboraf, changed the status of melanoma treatment. The US Food and Drug Administration (FDA) approved Mekinist (Trametinib), a treatment for advanced or unresectable melanoma, developed by GlaxoSmithKline (GSK) on May 29, 2013. Mekinist is the first MEK inhibitor as a single oral tablet and is suitable for the treatment of adult patients with unresectable melanoma or metastatic melanoma with BRAF V600E and V600K mutations. The BRAF V600E mutation accounts for approximately 85% of all BRAF V600 mutations in metastatic melanoma, and the V600K mutation accounts for approximately 10% of all BRAF V600 mutations in metastatic melanoma. In a mekinist trial involving 322 patients, the survival of patients treated with mekinist was increased by 3.3 months compared to patients receiving chemotherapy.

  Patent Document 1 discloses an oral solid preparation of the MEK inhibitor trametinib. In order to solve the harmful pharmacodynamic problems caused by stability, dissolution rate of solid dosage forms and desolvation of trametinib solvate upon in vivo administration, the excipients used in the solid dosage forms are substantially water soluble. Not included.

  Patent Document 2 discloses a powder formulation containing trametinib and a solubilizer. The solubilizer is selected from cyclodextrin-based formulation aids in order to solve the problems of dissolution rate of the powder formulation upon in vivo administration and desolvation of the trametinib solvate.

Patent Document 3 discloses 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) which is particularly useful for cancer treatment as an inhibitor of MEK activity. Oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof is disclosed. Patent Document 4 discloses 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine- Disclosed is crystal form I of 3-carboxamide p-toluenesulfonate (Compound A) and a process for its preparation.

  Pharmaceutically active compound forms with low solubility can face many challenges in the production of high quality solid pharmaceutical compositions or solid formulations (such as tablets, granules, and fine powders). None of the above references mentions how to solve such problems in order to provide compositions with low solubility of compound A and its salts and satisfactory dissolution rates.

CN103998041A CN104902876A WO2015058589 WO2016155473

Summary of the present invention

  The present invention provides 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6 as the active ingredient An oral solid pharmaceutical composition containing dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof and hydroxypropylmethylcellulose is provided. The properties of the pharmaceutical composition are improved and have rapid dissolution, good stability and acceptable dissolution and disintegration rates. They contribute to ensuring safe and effective drug therapy. In addition, the method for producing the pharmaceutical composition is simple and more suitable for industrial production.

  In one embodiment of the invention the active ingredient is 0.01 to 10% by weight, preferably 0.1 to 5% by weight and also 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, based on the weight of the pharmaceutical composition. 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.9, 3.0, 3.1, 3.2, It can be present in amounts of 3.3, 3.4, 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9 and 5.0% by weight.

  Further, the active ingredient 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy)-of the present invention in the oral solid pharmaceutical composition The weight of 6-oxo-1,6-dihydropyridine-3-carboxamide is 0.125 mg, 0.5 mg, 1 mg and 2 mg per 100 mg (100 mg / unit) of an oral solid pharmaceutical composition per unit; Alternatively, the weight of the pharmaceutically acceptable salt of the active ingredient of the present invention (eg, p-toluenesulfonate) in the pharmaceutical composition is 0.168 mg, 0.674 mg, 1.348 mg and 2.694 mg.

  Furthermore, the hydroxypropyl methylcellulose of the present invention is 0.5 to 10% by weight, preferably 1 to 5% by weight, based on the weight of the pharmaceutical composition, and 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, It is present in an amount of 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 and 5.0% by weight, more preferably 1.5 to 3% by weight.

  Furthermore, the weight of the hydroxypropyl methylcellulose of the present invention in the oral solid pharmaceutical composition is 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 100 mg (100 mg / unit) of the oral solid pharmaceutical composition per unit, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg and 3.0 mg.

  In order to ensure that the pharmaceutical composition has good dissolution characteristics, the active ingredient in the pharmaceutical composition of the present invention needs to be micronized before production in order to obtain the desired particle size. In one embodiment, the particle size of 90% of the active ingredient particles (which can be expressed as D90 or d (0.9)) is 50 μm or less, and 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 μm, preferably 10 μm or less.

  The pharmaceutical composition of the present invention may also contain at least one formulation auxiliary material selected from the group consisting of a filler, a disintegrant, a glidant, a lubricant and a coating agent.

  The term “relative to the weight of the pharmaceutical composition” of the present invention means that the calculation of the usage range of the active ingredient or other type of formulation auxiliary material is based on the weight of the tablet core without the coating agent. means. See Example 1 for details.

  Fillers provide a practically sized volume that can be processed to assemble tablets. Fillers also contribute to the processing and can improve the physical properties of the pharmaceutical composition such as fluidity, compressibility and hardness of solid formulations. The interaction between the filler and the active ingredient is of particular interest to those skilled in the art because the amount of filler used in the pharmaceutical composition is large and the filler is in direct contact with the active ingredient (or active compound). It is. The filler of the present invention is known or determined by those skilled in the art, and preferably may be at least one of mannitol, lactose, microcrystalline cellulose, pregelatinized starch, and calcium hydrophosphate. It is not limited to. The filler of the present invention is 30 to 95% by weight, preferably 50 to 94% by weight, and 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 based on the weight of the pharmaceutical composition. 70, 72, 76, 80, 82, 86, 88, 89, 90, 91, 92, 93 and 94% by weight.

  Furthermore, the weight of the filler of the present invention in the oral solid pharmaceutical composition was 80 mg, 81 mg, 82 mg, 83 mg, 84, per 100 mg (100 mg / unit) of the oral solid pharmaceutical composition per unit. mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg and 94 mg.

  In one embodiment of the invention, the filler is preferably at least one selected from the group consisting of mannitol and microcrystalline cellulose. Furthermore, the pharmaceutical composition of the present invention uses mannitol and microcrystalline cellulose as fillers. Here, the weight ratio of mannitol to microcrystalline cellulose is 1.5: 1 to 10: 1. In order to further improve the phenomenon of punch clogging in the tablet manufacturing process, the weight ratio of mannitol to microcrystalline cellulose is 1.8: 1 to 4: 1 and also 1.9: 1, 2: 1, 2.2: 1, 2.4. 1: 2.6: 1, 2.8: 1, 3: 1, 3.2: 1, 3.4: 1, 3.6: 1, 3.8: 1 and 4: 1.

  A disintegrant is used to promote the destruction or disintegration of the pharmaceutical composition after administration. The disintegrants of the present invention are known or determined by those skilled in the art. This includes starches, celluloses, gums, cross-linked polymers and foaming agents such as corn starch, potato starch, pregelatinized starch, modified corn starch, croscarvillose sodium, crospovidone, sodium starch glycolate, aluminum magnesium silicate HV, methylcellulose, fine cellulose Although it may be crystalline cellulose, cellulose, colloidal silicon dioxide, natural sponge, or cation exchange resin, it is not limited thereto. Preferably, it is at least one selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and low-substituted hydroxypropylcellulose. Moreover, the disintegrant of the present invention is 2 to 15% by weight based on the weight of the pharmaceutical composition, and 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8 , 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 and 15% by weight.

  Lubricants are usually used to facilitate processing, prevent the formulation material from sticking to the manufacturing equipment, reduce friction between particles, improve the flow rate of the dosage form, and help the dosage form exit the manufacturing equipment. Is used. The lubricants of the present invention are known or determined by those skilled in the art. This may be talc, stearic acid (magnesium stearate, calcium stearate, zinc stearate, etc.), polyethylene glycol, ethylene oxide polymer, liquid paraffin, sodium lauryl phosphate, leucine, sodium stearyl fumarate. It is not limited. Preferably magnesium stearate. At least one selected from the group consisting of stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate. The lubricant of the present invention is 0.1 to 5% by weight based on the total weight of the pharmaceutical composition, and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8 and 5 wt%, preferably present in an amount of 0.5 to 3 wt%. .

One embodiment of the present invention is:
a) 0.1-5% by weight of 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, 6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof,
b) 2-15% by weight of disintegrant,
c) 50-94% by weight filler,
d) 1.5 to 3% by weight of hydroxypropyl methylcellulose,
e) Provide a pharmaceutical composition optionally containing 0.5 to 3% by weight of a lubricant.
Here, the filler is preferably at least one selected from the group consisting of mannitol and microcrystalline cellulose. The disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low substituted hydroxypropylcellulose. The lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate.
Furthermore, the filler is obtained by mixing mannitol with microcrystalline cellulose. The weight ratio of the two formulation auxiliary materials is 1.5: 1 to 10: 1, preferably 1.8: 1 to 4: 1.

  In a specific embodiment, the pharmaceutical composition of the present invention can also comprise a coating agent. The coating agent (non-site specific release coating) is hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, or hydroxypropylcellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin or polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate -Methyl methacrylate copolymer dispersion, sugar alcohol-containing saccharide, sucrose, mannitol paste, or Opadry (trade name) may be used, but not limited thereto. Opadry is preferred.

  This invention also provides the manufacturing method of the pharmaceutical composition of this invention including the following processes. 1) 1-((6-Bromoquinolin-4-yl) thio) cyclobutylcarboxylic acid or a pharmaceutically acceptable salt thereof comprising a disintegrant and optionally a filler, binder, lubricant and glidant. Mixing with at least one pharmaceutical auxiliary material selected from the group, 2) granulating the mixture obtained in step 1) and subsequently tableting the obtained granules or filling them into capsules, or The mixture obtained in step 1) is compressed directly, or the mixture obtained in step 1) is directly filled into capsules. Furthermore, there is a coating step following the granulation step. The coating agent is Opadry, hydroxypropylmethylcellulose, ethylcellulose or polyvinyl alcohol, preferably Opadry.

  The granulation method used in the present invention may be wet granulation or dry granulation. When the wet granulation method is used, fluid bed granulation or high-speed shear wet granulation can be employed.

In a specific embodiment of the present invention, the steps of the high-speed shear granulation method are as follows.
1) 2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3- Mixing carboxamide or a pharmaceutically acceptable salt thereof with filler and disintegrant;
2) Add a solution of hydroxypropylmethylcellulose to the mixture of step 1) to prepare a soft material. The soft material is then wet crushed, dried and crushed,
3) Add lubricant to the granules obtained in step 2), mix them,
4) Compress the mixture obtained in step 3) into tablets.

In a specific embodiment of the invention, the steps of fluid bed granulation are as follows.
1) 2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3- Mixing carboxamide or a pharmaceutically acceptable salt thereof with filler and disintegrant;
2) After fluidizing the powder mixture obtained in step 1), a solution of hydroxypropylmethylcellulose is sprayed on the surface of the powder mixture. Then they are dried and crushed,
3) Add lubricant to the granules obtained in step 2), mix them,
4) Compress the mixture obtained in step 3) into tablets.

  In a preferred embodiment of the present invention, a high-speed shear granulation method and a fluidized bed granulation method are employed as granulation methods.

  The present invention relates to the active ingredient 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6- Also provided is an oral solid pharmaceutical composition containing dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, mannitol and microcrystalline cellulose. Here, the weight ratio of mannitol to microcrystalline cellulose is 1.5: 1 to 10: 1. This greatly improves the pharmaceutical composition. Furthermore, the weight ratio of mannitol to microcrystalline cellulose is 1.8: 1 to 4: 1, 1.9: 1, 2: 1, 2.2: 1, 2.4: 1, 2.6: 1, 2.8: 1, 3: 1 3.2: 1, 3.4: 1, 3.6: 1, 3.8: 1 and 4: 1. In the oral solid pharmaceutical composition of the present invention, mannitol and microcrystalline cellulose are both 30 to 95% by weight, preferably 50 to 94% by weight, and 50, 52% based on the weight of the pharmaceutical composition. , 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 76, 80, 82, 86, 88, 89, 90, 91, 92, 93 and 94% by weight.

  Furthermore, the oral weight of the filler of the present invention in the solid pharmaceutical composition is 80 mg, 81 mg, 82 mg, 83 mg, 84, per 100 mg (100 mg / unit) of the oral solid pharmaceutical composition per unit. mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg and 94 mg.

  The oral solid pharmaceutical composition (solid preparation) of the present invention may be a tablet, granule, powder (including fine granules) or capsule. The solid preparation can be obtained by a widely known production method. The maximum water content of the final dry granule after granulation is controlled to 3% or less, then the granule is filled into capsules or directly packaged as granules. When the dosage form is a tablet, the humidity of the tableting environment is controlled during the tableting process so that the water content of the final raw tablet is less than 3% (3% or less). The final composition is processed by vacuum drying so that the water content of the final composition is less than 3%.

  When the pharmaceutical composition of the present invention is a tablet, the tablet can be produced by compressing the granule obtained as described above. The pressure of compression can be determined within a suitable range, and is preferably 1 to 10 kN. The shape of the tablet is not particularly limited, but is preferably a lens shape, a disc shape, a circle shape, an ellipse shape (a caplet or the like), a teardrop shape, or a polygonal shape (a triangle or a rhombus). The manufactured tablets can be coated by spraying a suspension / solution of coating agent through a pan coater. After coating is complete, the moisture content of the final tablet is controlled to 3% or less by the drying process. The drying temperature may be 40-80 ° C, preferably 50-60 ° C. The drying method can be performed by ordinary oven drying or vacuum drying.

  When the pharmaceutical composition of the present invention is a granule, the granule obtained as described above can be used directly, or can be granulated into a desired granule by an appropriate technique. Furthermore, the granules thus produced can be coated by spraying a suspension / solution of coating agent.

  2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3 of the present invention -A pharmaceutically acceptable salt of carboxamide is p-toluenesulfonate.

  The dissolution rate of the pharmaceutical composition of the present invention is measured according to the second method (paddle method) of the dissolution rate test described in General Regulations 0931 of Volume 4 of the Chinese Pharmacopoeia 2015 edition. The dissolution test of the composition of the present invention is carried out at 37 ± 0.5 ° C. and a paddle speed of 50 rpm using pH 6.8 phosphate buffer, preferably 1000 ml pH 6.8 phosphate buffer as the dissolution medium. Elution rate up to 45 minutes is over 90%, even 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and over 100% Good. Further, it is preferably 94% or more.

  Furthermore, the elution rate up to 30 minutes is 80% or more, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% or more. Further, it is preferably 85% or more.

  2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3 of the present invention -Carboxamide can be obtained by the methods described in Patent Documents 3 and 4. All formulation auxiliary materials such as lactose and microcrystalline cellulose used in the present invention are commercially available.

2 shows the dissolution profile of the tablet of Example 1 in pH 6.8 phosphate buffer. Fig. 2 shows the dissolution profile of the tablet of Example 2 in pH 6.8 phosphate buffer. Fig. 5 shows the dissolution profile of the tablet of Example 4 in pH 6.8 phosphate buffer.

Detailed Description of the Invention

  The present invention is described in further detail using the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the invention.

実験例１〜４の錠剤の溶出率を中国薬局方2015年版第4巻の一般規則0931に記載されている溶出率試験の第二法（パドル法）に従って測定した。該溶出試験は、溶出媒体として1000 mlのpH6.8リン酸緩衝液を用いて、37±0.5℃およびパドル速度50 rpmで実施した。その結果、実験例１における化合物Ａの溶出は遅くかつ不完全であり、実験例２および３における化合物Ａの溶出は迅速ではあるが、不完全であり、また、実施例４における化合物Ａの溶出は迅速かつ完全であることが示されている。該溶出データを下の表２に示し、該溶出プロファイルを図１に示す。

According to the ratio shown in Table 1, 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, 6-Dihydropyridine-3-carboxamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose and croscarmellose sodium were wet granulated with a high-speed shear granulator. As a wetting agent, a 5% aqueous solution of povidone K30 or a 3% or 4% aqueous solution of hydroxypropylmethylcellulose was used. The wet soft material was wet crushed and dried, and then the dry granules (water content less than 3%) were dry crushed. A prescribed amount of magnesium stearate was added and mixed well with the granules. All the mixed granules obtained were compressed into tablets.

The dissolution rate of the tablets of Experimental Examples 1 to 4 was measured according to the second method (paddle method) of dissolution rate test described in General Regulations 0931 of Volume 4 of Chinese Pharmacopoeia 2015. The dissolution test was performed at 37 ± 0.5 ° C. and a paddle speed of 50 rpm using 1000 ml of pH 6.8 phosphate buffer as the dissolution medium. As a result, the elution of Compound A in Experimental Example 1 was slow and incomplete, while the elution of Compound A in Experimental Examples 2 and 3 was rapid but incomplete, and the elution of Compound A in Example 4 Has been shown to be quick and complete. The elution data is shown in Table 2 below and the elution profile is shown in FIG.

実験例４〜７の錠剤の溶出率を中国薬局方2015年版第4巻の一般規則0931に記載されている溶出率試験の第二法（パドル法）に従って測定した。該溶出試験は、溶出媒体として1000 mlのpH6.8リン酸緩衝液を用いて、37±0.5℃およびパドル速度50 rpmで実施した。その結果、実験例４〜７における溶出が完全であることが示されている。該溶出データを下の表４に示し、該溶出プロファイルを図２に示す。

According to the ratio shown in Table 3, 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, 6-Dihydropyridine-3-carboxamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose and croscarmellose sodium were wet granulated with a high-speed shear granulator. A 4% aqueous solution of hydroxypropylmethylcellulose was used as a wetting agent. The wet soft material was wet milled and dried, and then the dry granules (water content less than 3%) were dry milled. A prescribed amount of magnesium stearate was added and mixed well with the granules. All the mixed granules obtained were compressed into tablets.

The dissolution rate of the tablets of Experimental Examples 4 to 7 was measured according to the second method (paddle method) of the dissolution rate test described in General Regulations 0931 of Volume 4 of the Chinese Pharmacopoeia 2015 edition. The dissolution test was performed at 37 ± 0.5 ° C. and a paddle speed of 50 rpm using 1000 ml of pH 6.8 phosphate buffer as the dissolution medium. As a result, it is shown that elution in Experimental Examples 4 to 7 is complete. The elution data is shown in Table 4 below and the elution profile is shown in FIG.

2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide p -Toluenesulfonate (hereinafter referred to as Compound A) was passed through an 80-mesh sieve and pulverized with a Mcone jet mill (micronization pressure: 4 bar, sample introduction pressure: 6 bar). The particle size was measured directly using a Malvern laser particle size analyzer (Mastersizer 2000). The results are shown in Table 5 below.

2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridine-) treated according to the method of Example 3 according to the ratio of Experimental Example 4 shown in Table 1. 3-yl) oxy) -6-oxo-1,6-dihydropyridine-3-carboxamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose and croscarmellose sodium By wet granulation. A 4% aqueous solution of hydroxypropylmethylcellulose was used as a wetting agent. The wet soft material was wet-ground and dried, and then the dry granules (water content less than 3%) were dry-ground. A prescribed amount of magnesium stearate was added and mixed well with the granules. All the mixed granules obtained were compressed into tablets.
The dissolution rate of the tablet of Example 4 was measured according to the second method (paddle method) of the dissolution rate test described in General Regulations 0931 of Volume 4 of the Chinese Pharmacopoeia 2015 edition. The dissolution test was performed at 37 ± 0.5 ° C. and a paddle speed of 50 rpm using 1000 ml of pH 6.8 phosphate buffer as the dissolution medium. As a result, the particle size of the raw material pulverized by the jet mill is smaller than that of the raw material sieved by the 80 mesh sieve, which is 10 μm or less, and the sample manufactured from the raw material sieved by the 80 mesh sieve Elution is incomplete, and the elution rate of samples made from raw material micronized by a jet mill is clearly faster than the elution rate of samples made from raw material sieved by 80 mesh sieve. Shown to be complete. The elution data is shown in Table 6 below and the elution profile is shown in FIG.

実験例２では微結晶性セルロースの量が少なく、錠剤の製造過程においてパンチ詰まりの現象が発生した。実験例５では微結晶性セルロースの量が増え、パンチ詰まりの現象が改善された。実験例３ではパンチ詰まりの現象は全く発生しなかった。










According to the ratio shown in Table 1, 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, 6-Dihydropyridine-3-carboxamide p-toluenesulfonate (hereinafter referred to as Compound A), mannitol, microcrystalline cellulose and croscarmellose sodium were wet granulated with a high-speed shear granulator. A 3% aqueous solution of hydroxypropylmethylcellulose was used as a wetting agent. The wet soft material was wet crushed and dried, and then the dry granules (water content less than 3%) were dry crushed. A prescribed amount of magnesium stearate was added and mixed well with the granules. All the mixed granules obtained were compressed into tablets.

In Experimental Example 2, the amount of microcrystalline cellulose was small, and the phenomenon of punch clogging occurred in the tablet production process. In Experimental Example 5, the amount of microcrystalline cellulose increased and the phenomenon of punch clogging was improved. In Experimental Example 3, the phenomenon of punch clogging did not occur at all.

Claims (16)

  2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3 as active ingredient An oral solid pharmaceutical composition comprising carboxamide or a pharmaceutically acceptable salt thereof and hydroxypropylmethylcellulose, wherein the content of the active ingredient is preferably 0.01 to 10%, more preferably 0.1 to An oral solid pharmaceutical composition that is 5%.   The hydroxypropyl methylcellulose is present in an amount of 0.5 to 10% by weight, preferably 1 to 5% by weight, more preferably 1.5 to 3% by weight, based on the weight of the pharmaceutical composition. The pharmaceutical composition according to 1.   The pharmaceutical composition further comprises a filler, wherein the filler is at least one selected from the group consisting of mannitol, lactose, microcrystalline cellulose, pregelatinized starch and calcium hydrophosphate, preferably mannitol and At least one selected from the group consisting of microcrystalline cellulose, more preferably the filler contains mannitol and microcrystalline cellulose, and most preferably the weight ratio of mannitol to microcrystalline cellulose is The pharmaceutical composition according to claim 1 or 2, characterized in that it is 1.5: 1 to 10: 1, most preferably 1.8: 1 to 4: 1.   4. The pharmaceutical composition according to claim 3, characterized in that the filler is present in an amount of 30 to 95% by weight, preferably 50 to 94% by weight, based on the weight of the pharmaceutical composition.   The pharmaceutical composition further comprises at least one formulation auxiliary material selected from the group consisting of a disintegrant, a glidant, a lubricant and a coating agent. The pharmaceutical composition according to item.   The disintegrant is at least one selected from the group consisting of sodium carboxymethylcellulose, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropylcellulose, preferably 2 to 15 based on the weight of the pharmaceutical composition The pharmaceutical composition according to claim 5, characterized in that it is present in an amount of% by weight.   The lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate, preferably with respect to the weight of the pharmaceutical composition The pharmaceutical composition according to claim 5, characterized in that it is present in an amount of 0.1 to 5% by weight, more preferably 0.5 to 3% by weight.   Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pharmaceutically acceptable salt of the active ingredient is p-toluenesulfonate. An oral solid pharmaceutical composition containing the following ingredients:
a) 0.1-5% by weight of 2-((2-fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1, 6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof,
b) 2-15% by weight disintegrant, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, crospovidone and low substituted hydroxypropylcellulose;
c) 50-94% by weight filler, wherein the filler is at least one selected from the group consisting of mannitol and microcrystalline cellulose;
d) 1.5 to 3% by weight of hydroxypropyl methylcellulose, and
e) 0.5-3 wt% lubricant, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate. One.   The filler is composed of mannitol and microcrystalline cellulose, preferably the weight ratio of mannitol to microcrystalline cellulose is 1.5: 1 to 10: 1, more preferably 1.8: 1 to 4: 1. The pharmaceutical composition according to claim 9.   2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3 as active ingredient -An oral solid pharmaceutical composition comprising carboxamide or a pharmaceutically acceptable salt thereof, mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is 1.5: 1 to 10: 1 An oral solid pharmaceutical composition, preferably 1.8: 1 to 4: 1.   The content of the active ingredient is 0.01 to 10%, preferably 0.1 to 5%, and mannitol and microcrystalline cellulose are both 30 to 95% by weight, preferably 50 to 50%, based on the weight of the pharmaceutical composition. 12. A pharmaceutical composition according to claim 11, characterized in that it is present in an amount of 94% by weight.   The pharmaceutical composition further comprises hydroxypropylmethylcellulose, preferably the hydroxypropylmethylcellulose is 0.5 to 10% by weight, preferably 1 to 5% by weight, more preferably 1.5 to 3% by weight relative to the weight of the pharmaceutical composition. Pharmaceutical composition according to claim 11 or 12, characterized in that it is present in an amount of%.   The dissolution rate of the active ingredient is measured according to the second method (paddle method) of the dissolution rate test described in the General Regulations 0931 of the Chinese Pharmacopoeia 2015 Volume 4 Vol. The pharmaceutical composition according to any one of claims 1 to 13, characterized in that is 90% or more, preferably 94% or more.   The pharmaceutical composition according to claim 14, characterized in that the dissolution rate of the active ingredient for up to 30 minutes is 80% or more, preferably 85% or more. 1) 2-((2-Fluoro-4-iodophenyl) amino) -1-methyl-4-((6-methylpyridin-3-yl) oxy) -6-oxo-1,6-dihydropyridine-3- Mixing carboxamide or a pharmaceutically acceptable salt thereof with a disintegrant and optionally at least one formulation aid selected from the group consisting of fillers, binders, lubricants and glidants, and 2) Granulate the mixture obtained in 1) and then tablet the granules obtained or fill them into capsules, or directly tablet the mixture obtained in step 1) or step 1 The manufacturing method of the pharmaceutical composition of any one of Claims 1-15 including the process of directly filling a capsule with the mixture obtained by this.

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